Background: Enzymes of the FAH superfamily catalyze a multitude of diverse chemical reactions. Results: Using molecular modeling followed by biochemical investigations, FAHD1 was identified as oxaloacetate decarboxylase. Conclusion: Our findings suggest that ODx activity can be found in eukaryotic members of the FAH superfamily. Significance: Our results identify a mammalian ODx enzyme as a so far undescribed player in mitochondrial metabolism.
Methionine restriction (MetR) extends lifespan in animal models including rodents. Using human diploid fibroblasts (HDF), we report here that MetR significantly extends their replicative lifespan, thereby postponing cellular senescence. MetR significantly decreased activity of mitochondrial complex IV and diminished the accumulation of reactive oxygen species. Lifespan extension was accompanied by a significant decrease in the levels of subunits of mitochondrial complex IV, but also complex I, which was due to a decreased translation rate of several mtDNA-encoded subunits. Together, these findings indicate that MetR slows down aging in human cells by modulating mitochondrial protein synthesis and respiratory chain assembly.
Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescence in vitro, involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease.
The mitochondrial enzyme fumarylacetoacetate hydrolase domain-containing protein 1 (FAHD1) was identified to be upregulated in breast cancer tissues. Here, we show that FAHD1 is indispensable for the survival of BT-20 cells, representing the basal breast cancer cell type. A lentiviral knock-down of FAHD1 in the breast cancer cell lines MCF-7 and BT-20 results in lower succinate dehydrogenase (complex II) activity. In luminal MCF-7 cells, this leads to reduced proliferation when cultured in medium containing only glutamine as the carbon source. Of note, both cell lines show attenuated protein levels of the enzyme glutaminase (GLS) which activates programmed cell death in BT-20. These findings demonstrate that FAHD1 is crucial for the functionality of complex II in breast cancer cells and acts on glutaminolysis in the mitochondria.
Fumarylacetoacetate hydrolase
(FAH) superfamily members
are commonly expressed in the prokaryotic kingdom, where they take part in the
committing steps of degradation pathways of complex carbon sources. Besides FAH
itself, the only described FAH superfamily members in the eukaryotic kingdom are
fumarylacetoacetate hydrolase domain containing proteins
(FAHD) 1 and 2, that have been a focus of recent work in aging research. Here,
we provide a review of current knowledge on FAHD proteins. Of those, FAHD1 has
recently been described as a regulator of mitochondrial function and senescence,
in the context of mitochondrial dysfunction associated senescence (MiDAS). This
work further describes data based on bioinformatics analysis, 3D structure
comparison and sequence alignment, that suggests a putative role of FAHD
proteins as calcium binding proteins.
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